Nogo-A is secreted in extracellular vesicles, occurs in blood and can influence vascular permeability.

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability.

Extracellular Vesicles: Multimodal Envoys in Neural Maintenance and Repair.

The physiology of the central nervous system (CNS) is built on a foundation of connection, integration, and the exchange of complex information among brain cells. Emerging evidence indicates that extracellular vesicles (EVs) are key players in the intercellular communication that underlies physiological processes such as synaptic plasticity and the maintenance of myelination. Furthermore, upon injury to the CNS, EVs may propagate inflammation across the blood-brain barrier and beyond, and also appear to mediate neuroprotection and modulate regenerative processes. In neurodegenerative diseases, EVs may play roles in the formation, spreading, and clearance of toxic protein aggregates. Here, we discuss the physiological roles of EVs in the healthy and the diseased CNS, with a focus on recent findings and emerging concepts.